The purpose of this project is to identify the determinants of type 2 diabetes, obesity, and other chronic diseases in the Pima Indians, and elucidate their natural history. Genetic and environmental risk factors for type 2 diabetes have been studied. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Studies of the genetics of type 2 diabetes and obesity are described in project report # Z01 DK 69028 PECR. The potential role of inflammation in the pathogenesis of type 2 diabetes has been investigated. Serum concentrations of gamma globulin predicted the development of diabetes, supporting the inflammation hypothesis. This hypothesis is under further investigation in a case-control study of several markers of inflammation. A simple questionnaire for alcohol dependence (CAGE) has been validated in comparison with detailed psychiatric assessments and will be used to investigate the potential relationship of alcoholism with diabetes and its complications. The body mass index has been validated in comparison with dual energy x-ray absorptiometry as an index of obesity in children. In nondiabetic adults, a correlation between serum insulin concentrations and reported physical activity has been documented, consistent with the hypothesis that physical activity protects from diabetes by improving insulin action.